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Sreedharan, J.

Publications and source records attributed to Sreedharan, J..

2 recordsLinked to original sources

Revisiting Parameter Estimation in Biological Networks: Influence of Symmetries

AO_SCPLOWBSTRACTC_SCPLOWGraph models often give us a deeper understanding of real-world networks. In the case of biological networks they help in predicting the evolution and history of biomolecule interactions, provided we map properly real networks into the corresponding graph models. In this paper, we show that for biological graph models many of the existing parameter estimation techniques overlook the critical property of graph symmetry (also known formally as graph automorphisms), thus the estimated parameters give statistically insignificant results concerning the observed network. To demonstrate it and to develop accurate estimation procedures, we focus on the biologically inspired duplication-divergence model, and the up-to-date data of protein-protein interactions of seven species including human and yeast. Using exact recurrence relations of some prominent graph statistics, we devise a parameter estimation technique that provides the right order of symmetries and uses phylogenetically old proteins as the choice of seed graph nodes. We also find that our results are consistent with the ones obtained from maximum likelihood estimation (MLE). However, the MLE approach is significantly slower than our methods in practice.

systems biology

Neuronal hyperexcitability drives TDP43 pathology by upregulating shortened TDP43 protein isoforms

Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly-conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened (s) TDP43 splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.

neuroscience